RT Journal Article SR Electronic T1 Mutations in SETD2 cause a novel overgrowth condition JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 512 OP 517 DO 10.1136/jmedgenet-2014-102402 VO 51 IS 8 A1 Luscan, Armelle A1 Laurendeau, Ingrid A1 Malan, Valérie A1 Francannet, Christine A1 Odent, Sylvie A1 Giuliano, Fabienne A1 Lacombe, Didier A1 Touraine, Renaud A1 Vidaud, Michel A1 Pasmant, Eric A1 Cormier-Daire, Valérie YR 2014 UL http://jmg.bmj.com/content/51/8/512.abstract AB Background Overgrowth conditions are a heterogeneous group of disorders characterised by increased growth and variable features, including macrocephaly, distinctive facial appearance and various degrees of learning difficulties and intellectual disability. Among them, Sotos and Weaver syndromes are clinically well defined and due to heterozygous mutations in NSD1 and EZH2, respectively. NSD1 and EZH2 are both histone-modifying enzymes. These two epigenetic writers catalyse two specific post-translational modifications of histones: methylation of histone 3 lysine 36 (H3K36) and lysine 27 (H3K27). We postulated that mutations in writers of these two chromatin marks could cause overgrowth conditions, resembling Sotos or Weaver syndromes, in patients with no NSD1 or EZH2 abnormalities. Methods We analysed the coding sequences of 14 H3K27 methylation-related genes and eight H3K36 methylation-related genes using a targeted next-generation sequencing approach in three Sotos, 11 ‘Sotos-like’ and two Weaver syndrome patients. Results We identified two heterozygous mutations in the SETD2 gene in two patients with ‘Sotos-like’ syndrome: one missense p.Leu1815Trp de novo mutation in a boy and one nonsense p.Gln274* mutation in an adopted girl. SETD2 is non-redundantly responsible for H3K36 trimethylation. The two probands shared similar clinical features, including postnatal overgrowth, macrocephaly, obesity, speech delay and advanced carpal ossification. Conclusions Our results illustrate the power of targeted next-generation sequencing to identify rare disease-causing variants. We provide a compelling argument for Sotos and Sotos-like syndromes as epigenetic diseases caused by loss-of-function mutations of epigenetic writers of the H3K36 histone mark.